PROJECT SUMMARY Given the virtually infinite niches and time to expand, every evolutionary scenario possible has had a hand in shaping what we see today, perhaps independently many times and in many places. Arguably, one of the most powerful drivers of this evolutionary life process is the struggle between virus and host that has resulted in very diverse defensive strategies. Interestingly, while the cellular response to virus infection was thought to be uniform in any one given species, evidence is mounting that mammalian stem cells have a unique strategy to combat virus that is distinct from all other cells of the body. This observation is largely based on the finding that these cells can successfully block productive virus infection, despite lacking the capacity to produce or respond to Type I interferon. In this exploratory R21, we seek to ascertain the molecular basis for this activity. To this end, we focus on an ex vivo model using primary fibroblasts and reprogrammed induced pluripotent stem (iPS) cells in Aim 1 as well as an in vivo model to identify and characterize resident stem cells during a productive virus infection in Aim 2.